Autism is a neurodevelopmental disorder that develops in the first three years of life. It is probably caused by diverse genetic mutations that remain to be identified. Rett syndrome is a devastating form of autism spectrum disorders, and it is one of the few in which the underlying genetic cause, mutations on the MeCP2 gene, has been identified. MECP2 is a methyl-DNA binding protein that is thought to function as a transcriptional repressor. Despite immense efforts, only a few genes have been shown to be regulated by MECP2 in vivo. Here, we report that MECP2 regulates olfactory receptor expression, in an unusual way. In MeCP2 knockout mice olfactory receptor neurons express multiple olfactory receptors, in contrast to the wild type mice where only one olfactory receptor allele is expressed in each neuron. Interestingly, the olfactory receptor alleles that appear coexpressed in the MeCP2 knockout neurons are always members of the same chromosomal cluster. This observation suggests that MeCP2 functions as an insulator that could be regulating the monogenic expression of gene families that are organized in chromosomal clusters like the olfactory receptor genes. The violation of the "one receptor per neuron" rule provides a robust molecular assay for MeCP2 activity. We propose to use this assay in a high throughput screen of chemicals that can reverse the molecular consequences of MeCP2 deletion in dissociated olfactory neurons. These compounds could eventually be the basis for a pharmacological treatment of Rett syndrome symptoms. PUBLIC HEALTH RELEVANCE: This application proposes the use of a robust molecular phenotype that we discovered in MeCP2 knockout olfactory neurons, for a high throughput screen for compounds that restore the deficiencies caused by MeCP2 deletion. MeCP2 mutations are the main cause of Rett syndrome;therefore our application has significant relevance to the health and quality of life of Rett syndrome patients and their families.